A compound heterozygote for hepatic lipase gene mutations Leu334–>Phe and Thr383–>Met: correlation between hepatic lipase activity and phenotypic expression
| Autor: | Marju Tilly-Kiesi, P. Knudsen, Juhani Kahri, Marja-Riitta Taskinen, S. Lahdenperä, Christian Ehnholm, Antikainen M, H Tenkanen, A Bensadoun, M Uusi-Oukari, Ehnholm S |
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| Rok vydání: | 1996 |
| Předmět: |
Adult
Male Heterozygote DNA Complementary Molecular Sequence Data Mutant QD415-436 Biology Gene mutation Transfection Compound heterozygosity medicine.disease_cause Biochemistry Lipid Metabolism Inborn Errors Cell Line chemistry.chemical_compound Endocrinology medicine Animals Humans Point Mutation Child Finland Aged Mutation Base Sequence Wild type Lipase Cell Biology Lipids Molecular biology Pedigree Phenotype Liver chemistry Case-Control Studies Low-density lipoprotein Female Hepatic lipase Lipoprotein |
| Zdroj: | Europe PubMed Central Journal of Lipid Research, Vol 37, Iss 4, Pp 825-834 (1996) |
| ISSN: | 0022-2275 |
| DOI: | 10.1016/s0022-2275(20)37580-5 |
| Popis: | We have characterized the molecular basis for familial hepatic lipase (HL) deficiency in a Finnish family. In the propositus, the HL deficiency results from compound heterozygosity for two rare HL gene mutations, a previously unknown missense mutation designated L334F and the previously reported T383M mutation. These mutations were introduced into human HL cDNA by site-directed mutagenesis and the constructs expressed in COS-1 cells. In the homogenate of COS-1 cell transfected with the L334F mutant cDNA, a high amount of inactive protein accumulated. In the media of L334F transfected cells, 30% of the wild type activity and 80% of wild type mass were detected. The lysates of COS-1 cells transfected with the T383M mutant cDNA contained 39% of wild type HL activity and 34% of wild type HL mass. In the media of COS-1 cells transfected with the T383M cDNA construct, 50% of wild type HL mass but only 6% of wild type activity was present. The single amino acid substitutions present in L334F and T383M are therefore sufficient to severely affect the HL enzyme. These defects explain the HL-deficient phenotype of the individual carrying the two mutations. The lipoprotein phenotype associated with compound heterozygosity for L334F and T383M mutations is characterized by a slight increase in the buoyant low density lipoprotein (LDL) fraction and an increase in the light high density lipoprotein (HDL) fractions, HDL2a and HDL2b. These results demonstrate that lipoprotein changes occurring in HL deficiency are difficult to identify and support the hypothesis that HL is important in HDL remodeling and metabolism in vivo. |
| Databáze: | OpenAIRE |
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